CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays
| Autor: | Sudipto Roy, Noémi van Hul, Janine Altmüller, Hyungwon Choi, Nur'Ain Binte Ali, Xavier Bisteau, Shuhui Lim, Christian Windpassinger, Stéphane Blouin, Verena Rupp, Carine Bonnard, Franz Grill, Byrappa Venkatesh, Bruno Reversade, Rudolf Ganger, Vincenzo Coppola, S. Zakiah A. Talib, Klaus Klaushofer, Majid Alfadhel, Gökhan Yigit, Farid Ben Chehida, Paul Roschger, Ali Al Kaissi, Matias J. Caldez, Umut Altunoglu, Bernd Wollnik, Hülya Kayserili, Lionel Van Maldergem, Alvin Yu Jin Ng, Sameh A. Youssef, Lino Tessarollo, Katharina M. Roetzer, Hao Lu, Philipp Kaldis, Juliette Piard, Alain de Bruin, Sumanty Tohari |
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| Přispěvatelé: | Karabey, Hülya Kayserili, Wollnik, Bernd, Kaldis, Philipp, Windpassinger, Christian, Piard, Juliette, Bonnard, Carine, Alfadhel, Majid, Lim, Shuhui, Bisteau, Xavier, Blouin, Stéphane, Ali, Nur'Ain B., Ng, Alvin Yu Jin, Lu, Hao, Tohari, Sumanty, Talib, S. Zakiah A., van Hul, Noémi, Caldez, Matias J., Van Maldergem, Lionel, Yiğit, Gökhan, Youssef, Sameh A., Coppola, Vincenzo, de Bruin, Alain, Tessarollo, Lino, Choi, Hyungwon, Rupp, Verena, Roetzer, Katharina, Roschger, Paul, Klaushofer, Klaus, Altmüller, Janine, Roy, Sudipto, Venkatesh, Byrappa, Ganger, Rudolf, Grill, Franz, Ben Chehida, Farid, Altunoglu, Umut, Al Kaissi, Ali, Reversade, Bruno, School of Medicine, Department of Medical Genetics, Regenerative Medicine, Stem Cells & Cancer, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction & Development (AR&D), Center for Reproductive Medicine, ACS - Heart failure & arrhythmias, ACS - Diabetes & metabolism |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Developmental Disabilities medicine.disease_cause Mice 0302 clinical medicine Phosphorylation Child Genetics (clinical) Exome sequencing Cells Cultured Growth Disorders Mice Knockout Mutation Cultured Cilium Cell Cycle Disease gene identification Phenotype Cyclin-Dependent Kinases Pedigree Embryo 030220 oncology & carcinogenesis Child Preschool Female Signal Transduction medicine.medical_specialty Cells Knockout Biology Article 03 medical and health sciences Germline mutation Internal medicine Ciliogenesis Journal Article Genetics medicine Animals Humans Star syndrome Genome browser Protein-kinase Cdk10/Cyclin M Family Gene Pisslre DNA Melanoma Member Cilia Preschool Cell Proliferation Medicine Genetics and heredity Mammalian Infant Fibroblasts medicine.disease Embryo Mammalian Spine 030104 developmental biology Endocrinology Congenital disorder Al Kaissi syndrome knockout mice CDK10 ETS2 cilia congenital disorder growth retardation metabolism spine malformation |
| Zdroj: | American Journal of Human Genetics American journal of human genetics, 101(3), 391-403. Cell Press American Journal of Human Genetics, 101(3), 391. Cell Press |
| ISSN: | 0002-9297 |
| Popis: | In five separate families, we identified nine individuals affected by a previously unidentified syndrome characterized by growth retardation, spine malformation, facial dysmorphisms, and developmental delays. Using homozygosity mapping, array CGH, and exome sequencing, we uncovered bi-allelic loss-of-function CDK10 mutations segregating with this disease. CDK10 is a protein kinase that partners with cyclin M to phosphorylate substrates such as ETS2 and PKN2 in order to modulate cellular growth. To validate and model the pathogenicity of these CDK10 germline mutations, we generated conditional-knockout mice. Homozygous Cdk10-knockout mice died postnatally with severe growth retardation, skeletal defects, and kidney and lung abnormalities, symptoms that partly resemble the disease's effect in humans. Fibroblasts derived from affected individuals and Cdk10-knockout mouse embryonic fibroblasts (MEFs) proliferated normally; however, Cdk10-knockout MEFs developed longer cilia. Comparative transcriptomic analysis of mutant and wild-type mouse organs revealed lipid metabolic changes consistent with growth impairment and altered ciliogenesis in the absence of CDK10. Our results document the CDK10 loss-of-function phenotype and point to a function for CDK10 in transducing signals received at the primary cilia to sustain embryonic and postnatal development. NIH, the National Cancer Institute; Center for Cancer Research; Strategic Positioning Fund for the Genetic Orphan Diseases program; Industry Alignment Fund for the Singapore Childhood Undiagnosed Diseases program from the A*STAR (Agency for Science, Technology, and Research) Biomedical Research Council; A*STAR Biomedical Research Council |
| Databáze: | OpenAIRE |
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